Project Summary/Abstract Our long-term goal is to identify therapeutic agents that can prevent the pathogenesis of Alzheimer?s disease (AD). The number of AD cases is rising dramatically worldwide, and there is an urgent need to develop new therapies that are more efficacious than the four currently approved drugs for AD which provide only modest symptomatic relief. Every clinical trial to date has failed to demonstrate disease-modifying efficacy for AD, which may in part be due to our limited understanding of the mechanisms that precede the pathogenesis of AD, and that are distinct from normal healthy aging. The overall aims of our proposal are to further understand the mechanisms underlying dysregulation of the autophagy-inflammation network that becomes progressively dysregulated with age, and accelerated by pathological conditions. Systemic inflammation is a biomarker of this dysregulation, as exemplified by its prevalence in many aging-related disorders including cardiovascular disease, diabetes, cancers, and neuroinflammation in neurodegenerative disorders such Alzheimer?s disease (AD). We hypothesize that mechanisms which drive systemic inflammation are common to both the biology of aging and AD and propose that interventions which target the shared feature of systemic inflammation, via regulation of the autophagy-inflammation network, may have potential as therapeutic agents for the prevention of conversion to disease pathogenesis in AD, as well as improve healthspan and longevity in aging populations. For this proposal we will use a combination of genetic and pharmacological tools to understand which brain specific cell types may be involved in the regulation of the autophagy-inflammation network via both mTOR dependent and mTOR-independent mechanisms that modulate inflammation. Findings from our studies will provide mechanistic insights at a cellular level and innovative therapeutic strategies for further research. Specifically, we will investigate the individual cell types that contribute to the neuroprotective effects of mTOR inhibition in progressive AD, and confirm and extend the data on the beneficial effects of lifespan and healthspan in sporadic AD with prophylactic treatment of rapamycin. Critically, since age and genetics are the leading risk factors for AD, we will evaluate interventions in preclinical model systems that incorporate both aging and genetic risk factors for AD. We will therefore test the role of direct manipulation of AMPK on modulation of lifespan and healthspan in normal aging and in AD susceptible models, and the beneficial role of MAG lipase inhibition in normal healthy aging and in the pathogenesis of AD in comparison to the effects of rapamycin in a mouse model of late onset AD.